1-111238804-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004000.3(CHI3L2):c.790A>T(p.Met264Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,774 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: CHI3L2 NM_004000.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.219

Genes affected

CHI3L2 (HGNC:1933): (chitinase 3 like 2) The protein encoded by this gene is similar to bacterial chitinases but lacks chitinase activity. The encoded protein is secreted and is involved in cartilage biogenesis. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Apr 2012]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21962446).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHI3L2	NM_004000.3	c.790A>T	p.Met264Leu	missense_variant	8/11	ENST00000369748.9
CHI3L2	NM_001025197.1	c.760A>T	p.Met254Leu	missense_variant	7/10
CHI3L2	NM_001025199.2	c.553A>T	p.Met185Leu	missense_variant	7/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHI3L2	ENST00000369748.9	c.790A>T	p.Met264Leu	missense_variant	8/11	1	NM_004000.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000796 AC: 2 AN: 251256 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135818

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461774 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 727188

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 05, 2023

The c.790A>T (p.M264L) alteration is located in exon 8 (coding exon 8) of the CHI3L2 gene. This alteration results from a A to T substitution at nucleotide position 790, causing the methionine (M) at amino acid position 264 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.50
Cadd	Benign	15
Dann	Benign	0.89
DEOGEN2	Benign	0.0094	T;.;T;.;.
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.15
FATHMM_MKL	Benign	0.35	N
M_CAP	Benign	0.0086	T
MetaRNN	Benign	0.22	T;T;T;T;T
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	-0.31	N;.;N;.;.
MutationTaster	Benign	0.82	N;N;N;N;N
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.72	N;N;N;N;N
REVEL	Benign	0.098
Sift	Benign	0.42	T;T;T;T;T
Sift4G	Benign	0.61	T;T;T;T;T
Polyphen		0.83	P;.;P;.;.
Vest4		0.27
MutPred		0.57		Gain of catalytic residue at M264 (P = 0.0076);.;Gain of catalytic residue at M264 (P = 0.0076);.;.;
MVP		0.10
MPC		0.021
ClinPred		0.20	T
GERP RS		3.4
Varity_R		0.24
gMVP		0.37

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs745539496; hg19: chr1-111781426;